This grant utilizes tissue engineering to examine endothelial cell physiology on one hand and the basis of cardiovascular diseases on the other. The two are interrelated. The intact endothelium regulates all aspects of vascular biology, insures vascular quiescence and regulates vascular repair. Many cardiovascular diseases appear to begin with and propagate through disruption of the endothelial defense mechanisms. Yet, it is not clear whether endothelial control arises from the physical presence of the endothelium at the lumenal border or from the compounds intact endothelial cells secrete. The answer to this question may dictate how we understand, diagnose, design new therapies for and treat the full gamut of vascular disease. This proposal seeks to understand better the biochemical role of the endothelial cell in regulating vasoproliferative diseases, above and beyond that established by the physical barrier forces established by the endothelium at the luminal interface. Our work with tissue-engineered endothelial cell implants has helped to add to understanding in this area. Endothelial cells are embedded within sponge-like polymeric materials whose three dimensional configuration insures that large number of cells can be placed in a protective scaffolding adjacent to target tissues. We have characterized the cell secretory activity of embedded cells, and have demonstrated their retention of endothelial growth characteristics, immune identity and viability within the polymeric devices. When implanted around injured arteries the expected proliferative lesions are dramatically reduced. These grafts allow us to divorce structure from function and in particular will enable exploration of two groups of aims with a series of experiments. These aims include: 1. Determination of which of the phases of the vascular response to deep injury in higher species animal models are regulated by endothelial cell grafts. 2. elucidation of the biochemical synthetic functions that underlie engrafted endothelial cell control of vascular repair in vivo. This program is the first opportunity we will have to bring many diverse disciplines together to address these issues. We hope that the lessons learned will be utilized in the broadest context of fundamental cell and molecular biology of the vascular pathophysiology of disease, and for the continued creation and application of innovative molecular, cellular and pharmacological therapies for cardiovascular disease.